OP0043 TOCILIZUMAB SIGNIFICANTLY REDUCES SERUM AMYLOID A IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER – DATA FROM THE PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND TOFFIFE STUDY
Authors: J. Henes, S. Saur, D. M. Kofler, C. Kedor, C. Meisner, M. Krusche, I. Kötter, T. Xenitidis, H. Schulze-Koops, E. Feist
Journal: Annals of the Rheumatic Diseases (2022)

Background Uncontrolled inflammation in patients with familial Mediterranean fever (FMF) can lead to severe organ failure due to amyloidosis. Colchicine is still the standard treatment and the only therapy that has been proven to reduce the risk for amyloidosis. Besides colchicine the Interleukin (IL)1-antagonists Anakinra and Canakinumab are approved, but new treatment options are still needed. The IL-6 antagonist Tocilizumab (TCZ) effectively reduces inflammation and is approved in several other rheumatic indication. Here we present data from our phase II study TCZ for the treatment of FMF – TOFFIFE. Objectives To explore the efficacy and safety of tocilizumab in FMF. Methods The TOFFIFE study was a placebo-controlled, double-blinded, randomized trial to investigate the efficacy and safety of TCZ in patients with colchicine resistant (cr)FMF. The physician’s global assessment of disease activity (PGA) based on a 5 point-scale for 6 symptoms (range 0-24) was used as a clinical score and had to be &gt;2 at screening. Patients were randomized 1:1 to either receive monthly TCZ intravenously with 8 mg/kg bodyweight or placebo over a period of 24 weeks. Patients with inadequate response after week 12 had the opportunity to receive open label TCZ at week 16. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA ≤ 2 + normalized ESR or CRP (the item that led to inclusion had to be normalized) + normalized SAA. Secondary endpoints included normalization of SAA during treatment and safety of TCZ in FMF patients. Results 25 patients were randomized with a median age of 31 years (range 18 - 53y), of which 14 (56%) were female. At week 16, which was the timepoint for the primary end point, 2 (15.4%) patients in the TCZ arm reached the primary end point with a PGA ≤ 2 and normalization of SAA and CRP and/or ESR but none of the patients in the placebo arm. Therefore, the superiority of TCZ compared to placebo could be shown concerning the pre-specified significance level of α=0.2 (p=0.089). SAA levels normalized with TCZ but not with PBO. This difference between TCZ und PBO was highly significant; SAA p &lt; 0.015. At week 28 with 17 remaining patients and after having had the opportunity for a rescue treatment at week 16, the responder rates (PGA ≤ 2 + normalization of SAA, ESR and/or CRP) were 25% (n=1) in those patients who changed from placebo to TCZ (n=4) and 20% (n=2) in those patients who continued with TCZ (n=10). Of note, all 3 patients remaining on PBO were non-responders (p= 0.642). In 75% of patients (n=3) CRP and in 50% SAA (n=2) normalized after changing to TCZ. No new safety aspects occurred. Conclusion In this first randomized, placebo-controlled study in patients with active crFMF TCZ significantly reduced and normalized SAA levels. The trial met the primary endpoint to demonstrate the superiority of TCZ over PBO although only a small numerical difference was found. Nevertheless, the proportion of patients with a successful TCZ-therapy was lower than expected due to very strict response criteria; patients had to achieve a complete remission with a PGA ≤2 (on a 0-24 scale) and normalization of the inflammatory parameters (CRP/ESR and SAA). This required no or only mildest symptoms during the last 4 weeks. A larger multicenter study is therefore justifiable and needs to clarify the benefit of TCZ treatment in FMF. Figure 1. Secondary endpoint: Serum Amyloid A over time, showing a clear reduction in the TCZ but not in the PBO arm and rerise of SAA after discontinuation after week 28. Normal SAA value = &lt; 10mg/l. Outliers &gt; 100mg/l were excluded in this graph. Disclosure of Interests Jörg Henes Speakers bureau: SOBI, Novartis, Roche/Chugai, Consultant of: SOBI, Novartis, Roche/Chugai, Grant/research support from: SOBI, Novartis, Roche/Chugai, Sebastian Saur: None declared, David M Kofler: None declared, Claudia Kedor: None declared, Christoph Meisner: None declared, Martin Krusche Speakers bureau: SOBI, Novartis, Roche/Chugai, Ina Kötter Speakers bureau: SOBI, Novartis, Roche/Chugai, Consultant of: SOBI, Novartis, Roche/Chugai, Theodoros Xenitidis: None declared, Hendrik Schulze-Koops Speakers bureau: SOBI, Novartis, Roche/Chugai, Consultant of: SOBI, Novartis, Roche/Chugai, Eugen Feist Speakers bureau: SOBI, Novartis, Roche/Chugai, Consultant of: SOBI, Novartis, Roche/Chugai.